1. Field of the Invention:
This invention is concerned with new compounds of the formula: ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, halogen, hydroxymethyl, formyl, --COOH and alkyl-(C.sub.1 -C.sub.3); R.sub.2 and R.sub.3 may be the same or different and are selected from the group consisting of ##STR2## --N-[alkyl(C.sub.1 -C.sub.4)].sub.2 and ##STR3## with the proviso that at least one of R.sub.2 and R.sub.3 must be in the N-oxide form, together with the pharmaceutically acceptable salts thereof.
In addition, the current invention is concerned with a method of treating the immune response system in a warm-blooded animal which comprises administering to said animal an effective amount of a compound selected from the compounds described hereinabove in association with a pharmaceutically acceptable carrier, adjuvant or diluent.
2. Description of the Prior Art:
The use of immunomodulants and chemotherapeutic adjuvants constitutes a new therapeutic approach to the treatment of immune deficiencies and cancer and is based on the concept that there are distinctive antigens in or on most tumor cells (embryonal or transplantation antigens) that distinguish them from normal host cells. A majority of tumor immunologists favor the view that potentially malignant cells constantly arise but, because of their "foreignness", they are normally eliminated by a competent humoral and cellular immune system. Occasionally, however, tumor cells escape this immune surveillance and continue to reproduce and cancer results. The reason for the failure of the normally efficient immune surveillance mechanisms is not fully understood but it is thought that the immune system becomes less effective with increasing age. It is depressed in certain genetic immunodeficiency diseases, in various bacterial, fungal or viral infections and in patients undergoing immuno-suppressive therapy. The growth of the neoplasm itself, as well as the various therapeutic modalities designed to treat the disease, e.g., cytotoxic chemotherapy and radiation, leads to a still greater depression of host resistance and results in an increased susceptibility to both exogenous and endogenous infections and perhaps accounts for the re-initiation of tumor growth and metastasis which frequently follows treatment-induced tumor regression.
If depression of the immune system can result in the growth of malignancies, regulation of any facet of the immune response may help the host to eliminate residual cancer cells. Therefore, it is desirable to search for chemical agents (i.e., immunoregulants) capable of restoring and stimulating host immune defense mechanisms in order to overcome the deficiencies which account for susceptibility to disease and failure to eradicate the cancer. Such immunoregulating agents would likely be incapable of arresting the growth of a large tumor but their clinical utility would derive from their capacity to enhance normal immune surveillance mechanisms in patients whose tumor burden has been reduced by surgical, radiotherapeutic or chemotherapeutic methods.
Experimental studies in animals have demonstrated the antitumor potential of a number of immunoregulants including live organisms of bacillus Calmett-Guerin (BCG), heat-killed cells of Corynebacterium parvum, polynucleotides, and the anthelmintic drug, levamisole. These substances have been shown to stimulate cellular immunity and to produce tumor regression. Some successes have been claimed in early clinical trials with BCG against malignant melanoma and acute leukemia and with levamisole against lung cancer and breast cancer. Although the antitumor effects produced by these agents have been promising, significant therapeutic benefits have yet to be realized. Since this is a new therapeutic approach, new drugs and methods of treatment must receive careful clinical evaluation in order to reveal their full potential.
Modern research is directed to the discovery of a drug similar to, but more potent than, known immunoregulants such as levamisole that would be effective in the eradication of tumor cells when used in conjunction with standard therapeutic measures. Stimulators of host resistance may be detected in animal models that can, in fact, detect both immunostimulators and anticancer agents. Mice are put in a condition simulating immunodepression common to cancer patients. This is accomplished by infecting mice with a leukemia virus which produces both leukemia and a disease-related immunodepression. Effective drugs are recognized by their ability to restore or enhance the antibody response in the experimental mice, or to inhibit tumor progression.
Certain synthetic and naturally derived compounds have the ability to induce high levels of circulating interferon. Among these are bacterial endotoxins, intact bacteria and viruses, transplantable tumor cells and a variety of high and low molecular weight synthetic compounds such as poly I:C, tilorone and pyran copolymer [W. E. Stewart, The Interferon System, Springer-Verlag, Wein, New York (1979)]. Interferon has a major regulatory function in modulating cellular and humoral immune responses. Interferon and inducers of interferon "activate" macrophages to destroy tumor and virus infected cells, stimulate populations of immune cells to secrete lymphokines, protect against lethal infection by viruses and some bacterial species and stimulate the level of natural killer lymphocyte (NK-cell) activity in animals [Herberman, R. B. and Holden, H. T., Natural Cell-Mediated Immunity, Adv. Cancer Res., 27, 305-377 (1978) and Natural Killer Cells as Antitumor Effector Cells, J. Nat. Cancer Inst., 62 (3), 441-445 (1979)]. NK-cells play a major roll in immune surveillance in that they mediate the destruction of virus infected cells and a wide variety of syngeneic, allogeneic and xenogeneic tumor cells when tested in vitro (Herberman, R. B. and Holden, H. T., vide supra). The role of NK-cells in protecting animals against virus infection appears certain. The compounds of this invention are authentic modulators of humoral and cellular immunity in mice. The compounds induce high levels of circulating interferon, restore antibody production in immuno-suppressed mice, protect against lethal virus infection and stimulate NK-cell cytotoxicity for tumor cells.
It is a further object of this invention to provide a method of treating the immune system in a warm-blooded animal with compounds of this invention. More especially, it is an object of this invention to provide a method of treating the immune system in a warm-blooded animal with compounds of this invention in association with a pharmaceutically acceptable carrier, adjuvant or diluent.